Transmissible spongiform encephalopathies (TSE) are fatal neurodegenerative diseases which include bovine spongiform encephalopathy (BSE or mad cow disease), Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep. A central event in the pathogenesis of TSE diseases is the conversion of normal prion protein (PrP-sen) to an abnormal protease-resistant form (PrP-res). To learn how this occurs, we developed the first in vitro reaction showing that PrP-res itself can directly induce the conversion of PrP-sen to PrP-res. This reaction is highly specific in ways that provide a possible molecular basis for important biological aspects of TSE diseases including transmissibility, barriers to interspecies transmission and the existence of agent strains. In the past year we have extended our understanding of several aspects of this fundamental PrP conversion reaction and how it relates to TSE biology.